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Taste stem/progenitor cells from posterior mouse tongues have been used to generate taste bud organoids. However, the inaccessible location of taste receptor cells is observed in conventional organoids. In this study, we established a suspension-culture method to fine-tune taste bud organoids by apicobasal polarity alteration to form the accessible localization of taste receptor cells. Compared to conventional Matrigel-embedded organoids, suspension-cultured organoids showed comparable differentiation and renewal rates to those of taste buds in vivo and exhibited functional taste receptor cells and cycling progenitor cells. Accessible taste receptor cells enabled the direct application of calcium imaging to evaluate the taste response. Moreover, suspension-cultured organoids can be genetically altered. Suspension-cultured taste bud organoids harmoniously integrated with the recipient lingual epithelium, maintaining the taste receptor cells and gustatory innervation capacity. We propose that suspension-cultured organoids may provide an efficient model for taste research, including taste bud development, regeneration, and transplantation.

Abstract The aim of this study is to examine the dorsal lingual epithelium of the peregrine falcon (Falco peregrinus) of the family Falconidae. The tongue in its dorsal, lateral and ventral surfaces is covered with a non-keratinized multilayered stratified squamous epithelium. Lamina propria is present beneath the epithelial layers. Morphometrically, thickness of the apex tongue epithelium is more than that in the tongue body. Thickness of the ventral surface of the tongue is less than that in the dorsal one. Thickness of the lateral surface of the tongue was thicker than that in the ventral one and tongue body. Large and small conical papillae appeared on the posterior dorsal surface of the lingual body. There are lingual glands in certain areas of tongue body with numerous openings through the dorsal surface. Resumo O objetivo deste estudo é examinar o epitélio lingual dorsal do falcão peregrino (Falco peregrinus) da família Falconidae. A língua em suas superfícies dorsal, lateral e ventral é coberta por um epitélio escamoso estratificado de múltiplas camadas não queratinizado. A lâmina própria está presente abaixo das camadas epiteliais. Morfometricamente, a espessura do epitélio do ápice da língua é maior do que a do corpo da língua. A espessura da superfície ventral da língua é menor do que a dorsal. A espessura da face lateral da língua foi mais espessa do que na ventral e no corpo da língua. Papilas cônicas grandes e pequenas apareceram na superfície posterior dorsal do corpo lingual. Existem glândulas linguais em certas áreas do corpo da língua com numerosas aberturas na superfície dorsal.

The Hedgehog (HH) pathway regulates embryonic development of anterior tongue taste fungiform papilla (FP) and the posterior circumvallate (CVP) and foliate (FOP) taste papillae. HH signaling also mediates taste organ maintenance and regeneration in adults. However, there are knowledge gaps in HH pathway component expression during postnatal taste organ differentiation and maturation. Importantly, the HH transcriptional effectors GLI1, GLI2 and GLI3 have not been investigated in early postnatal stages; the HH receptors PTCH1, GAS1, CDON and HHIP, required to either drive HH pathway activation or antagonism, also remain unexplored. Using lacZ reporter mouse models, we mapped expression of the HH ligand SHH, HH receptors, and GLI transcription factors in FP, CVP and FOP in early and late postnatal and adult stages. In adults we also studied the soft palate, and the geniculate and trigeminal ganglia, which extend afferent fibers to the anterior tongue. Shh and Gas1 are the only components that were consistently expressed within taste buds of all three papillae and the soft palate. In the first postnatal week, we observed broad expression of HH signaling components in FP and adjacent, non-taste filiform (FILIF) papillae in epithelium or stroma and tongue muscles. Notably, we observed elimination of Gli1 in FILIF and Gas1 in muscles, and downregulation of Ptch1 in lingual epithelium and of Cdon , Gas1 and Hhip in stroma from late postnatal stages. Further, HH receptor expression patterns in CVP and FOP epithelium differed from anterior FP. Among all the components, only known positive regulators of HH signaling, SHH, Ptch1 , Gli1 and Gli2 , were expressed in the ganglia. Our studies emphasize differential regulation of HH signaling in distinct postnatal developmental periods and in anterior versus posterior taste organs, and lay the foundation for functional studies to understand the roles of numerous HH signaling components in postnatal tongue development.

Telocytes have recently emerged as unique interstitial cells defined by their extremely long, thin and moniliform prolongations termed telopodes. Despite growing evidence that these cells consistently reside in the stromal compartment of various organs from human beings, studies dealing with telocytes in structures of the oral cavity are scarce. Hence, the present morphologic study was undertaken to explore for the first time the presence and specific localization of telocytes within tissues of the normal human tongue, a complex muscular organ whose main functions include taste, speech, and food manipulation in the oral cavity. Telocytes were initially identified by CD34 immunostaining and confirmed by CD34/PDGFRα double immunofluorescence and transmission electron microscopy. CD34+/PDGFRα+ telocytes were organized in interstitial meshworks either in the tongue lamina propria or in the underlying striated muscle. Lingual telocytes were immunonegative for CD31, c-kit and α-SMA. Telopodes were finely distributed throughout the stromal space and concentrated beneath the lingual epithelium and around CD31+ vessels, skeletal muscle bundles/fibers, and intramuscular nerves and ganglia. They also enveloped salivary gland units outside the α-SMA+ myoepithelial cells and delimited lymphoid aggregates. These findings establish telocytes as a previously overlooked interstitial cell population worth investigating further in the setting of human tongue pathophysiology.

The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH) and retinoic acid (RA) signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity.

The current study was designed to investigate the effects of zinc sulfate on cell proliferation, metallothionein (MT) immunoreactivity and antioxidant system against acute ethanol-induced oxidative damage in tongue tissues of rats. Wistar albino male rats, 2.5 to 3.0 months, were divided into four groups: Group I (n = 8), intact control rats; group II (n = 8), control animals given only zinc sulfate (100 mg/kg/day, for 3 consecutive days); group III (n = 14), animals given 1 mL absolute ethanol; group IV (n = 11), animals given zinc sulfate and absolute ethanol at the same dose and time. Animals were sacrificed under anesthesia 2 h after ethanol administration or 4 h after the last zinc sulfate treatment. Ethanol administration caused a marked decrease in the number of MT immunopositive cells and the proliferating cells in the lingual epithelium. A statistically significant decline in reduced glutathione levels, catalase activity and superoxide dismutase activities was also observed, whereas a significant elevation of lipid peroxidation levels and lactate dehydrogenase activities was detected in the ethanol group. In contrast, these changes were reversed by administration of zinc sulfate to ethanol-treated rats. In conclusion, it shows that zinc sulfate has therapeutic effects on acute ethanol-induced oxidative damage in the tongue tissues of rats.

Despite the strong need for the establishment of a lingual epithelial cell culture system, a simple and convenient culture method has not yet been established. Here, we report the establishment of a novel lingual epithelium organoid culture system using a three-dimensional matrix and growth factors. Histological analyses showed that the generated organoids had both a stratified squamous epithelial cell layer and a stratum corneum. Very recently, we showed via a multicolor lineage tracing method that Bmi1-positive stem cells exist at the base of the epithelial basal layer in the interpapillary pit. Using our new culture system, we found that organoids could be generated by single Bmi1-positive stem cells and that in the established organoids, multiple Bmi1-positive stem cells were generated at the outermost layer. Moreover, we observed that organoids harvested at an early point in culture could be engrafted and maturate in the tongue of recipient mice and that the organoids generated from carcinogen-treated mice had an abnormal morphology. Thus, this culture system presents valuable settings for studying not only the regulatory mechanisms of lingual epithelium but also lingual regeneration and carcinogenesis.

Many commonly prescribed chemotherapy drugs such as cyclophosphamide (CYP) have adverse side effects including disruptions in taste which can result in loss of appetite, malnutrition, poorer recovery and reduced quality of life. Previous studies in mice found evidence that CYP has a two-phase disturbance in taste behavior: a disturbance immediately following drug administration and a second which emerges several days later. In this study, we examined the processes by which CYP disturbs the taste system by examining the effects of the drug on taste buds and cells responsible for taste cell renewal using immunohistochemical assays. Data reported here suggest CYP has direct cytotoxic effects on lingual epithelium immediately following administration, causing an early loss of taste sensory cells. Types II and III cells in fungiform taste buds appear to be more susceptible to this effect than circumvallate cells. In addition, CYP disrupts the population of rapidly dividing cells in the basal layer of taste epithelium responsible for taste cell renewal, manifesting a disturbance days later. The loss of these cells temporarily retards the system's capacity to replace Type II and Type III taste sensory cells that survived the cytotoxic effects of CYP and died at the end of their natural lifespan. The timing of an immediate, direct loss of taste cells and a delayed, indirect loss without replacement of taste sensory cells are broadly congruent with previously published behavioral data reporting two periods of elevated detection thresholds for umami and sucrose stimuli. These findings suggest that chemotherapeutic disturbances in the peripheral mechanisms of the taste system may cause dietary challenges at a time when the cancer patient has significant need for well balanced, high energy nutritional intake.

Many organs have been described as involved in long-COVID processes. Concerning the stomach, few cases have been reported and discussed. Particularly, we have very few information about the potential direct damage to the gastric mucosa caused by SARS-CoV-2. We report the case of a 45-year-old Italian woman with no known chronic diseases or food intolerances who developed severe gastrointestinal manifestations as long COVID-19 manifestation following a SARS-CoV-2 infection. During the acute phase of COVID-19, she exhibited, among other symptoms including respiratory ones, an intense vasculitis affecting the superficial veins of the lower limbs and near-total desquamation of the lingual epithelium. Treatment with corticosteroids (betamethasone) led to complete remission in a few days. However, after recovery, she suddenly developed worsening heartburn and esophageal reflux. A year later, she was diagnosed with severe gastritis and mild dysplasia of the gastric body. Anamnesis revealed new-onset food intolerances to gluten-containing food and dairy foods. Histological examination showed Helicobacter pylori (HP) infection. After eradication therapy and dietary modifications, her gastric inflammation regressed, and dysplasia resolved. We hypothesize that SARS-CoV-2 may have triggered disruption of the gastric mucosa homeostasis, in turn leading to both food intolerances and HP proliferation. This case raises the question of whether SARS-CoV-2-induced molecular mimicry mechanisms may have long-term consequences on the gastric muco-microbiotic layer and in turn on the whole gastric homeostasis.

The dorsal lingual epithelium, which is composed of taste buds and keratinocytes differentiated from K14+ basal cells, discriminates taste compounds and maintains the epithelial barrier. N6-methyladenosine (m6A) is the most abundant mRNA modification in eukaryotic cells. How METTL3-mediated m6A modification regulates K14+ basal cell fate during dorsal lingual epithelium formation and regeneration remains unclear. Here we show knockout of Mettl3 in K14+ cells reduced the taste buds and enhanced keratinocytes. Deletion of Mettl3 led to increased basal cell proliferation and decreased cell division in taste buds. Conditional Mettl3 knock-in mice showed little impact on taste buds or keratinization, but displayed increased proliferation of cells around taste buds in a protective manner during post-irradiation recovery. Mechanically, we revealed that the most frequent m6A modifications were enriched in Hippo and Wnt signaling, and specific peaks were observed near the stop codons of Lats1 and FZD7. Our study elucidates that METTL3 is essential for taste bud formation and could promote the quantity recovery of taste bud after radiation.